Advances in genetics have illustrated that autism spectrum disorder (ASD) and intellectual disability (ID) include a spectrum of rare disorders, and that mutations in hundreds of genes may result in susceptibility to ASD/ID. This heterogeneity represents significant challenges, but at the same time unique opportunities for research in the field of ASD/ID. Many of the genes implicated in ASD/ID appear to converge on a few common pathways, suggesting that there may be a common dysfunction at the cellular or systems level. Deeper understanding of the shared pathophysiology of these diseases may serve as gateways for understanding mechanisms of other causes of ASD/ID and for shared treatment possibilities. The Developmental Synaptopathies Consortium (DSC) was formed and funded in 2014 in order to perform mechanistic analysis of three genetic disorders with high penetrance of ASD/ID, and shed light on molecular pathways and mechanism-based therapeutic targets relevant to ASD/ID. We propose to continue our focus on three genetic syndromes with abnormal synapse structure or function and that are associated with high penetrance for ASD/ID: TSC1/2 (Tuberous Sclerosis Complex or TSC), PTEN (PTEN Hamartoma Tumor Syndrome or PHTS) and SHANK3 (Phelan McDermid Syndrome or PMS) mutations. Specific aims for TSC are: 1) Characterize the phenotype of ASD and ID in a large cohort of pediatric and adult patients with TSC in a prospective, multi-center longitudinal design; 2) Identify electrophysiological biomarkers of synaptic function and connectivity associated with ASD and ID in TSC; and 3) Evaluate the suitability of the TAND Checklist as TSC-specific research tool for assessing clinically-meaningful outcomes in future ASD and ID clinical trials. Specific aims for PHTS are: 1) Determine cross-sectional and longitudinal neurobehavioral and medical differences between PTEN-ASD and other groups in an expanded age range; 2) Identify EEG and molecular biomarkers specific to PTEN-ASD and those shared with other groups; and 3) Validate TAND and develop a comprehensive, multi-level, longitudinal model of PTEN-ASD using data from Aims 1 and 2 and TAND scores, in order to inform future clinical trials and the development of consensus care guidelines. Specific aims for PMS are: 1) Comprehensively characterize PMS across the lifespan and track the natural history; 2) Validate electrophysiological biomarkers of PMS; and 3) Develop a comprehensive clinical model of PMS to inform assessment and future clinical trials. As detailed in the Resources sections, this Consortium involves experienced physician-researchers from premier academic institutions with strong institutional and patient advocacy group support, along with impressive mentors for training of future physician- researchers and genetic counselors focused on translational research in neurodevelopmental disorders. We will continue to work closely with the patient advocacy groups to engage and inform the families affected with these disorders. Knowledge gained from this project will inform clinical practice and spur the development of novel treatments.